The catalytic diversity of biological systems provides enormous potential for application of living cells to the scalable production of pharmaceuticals, fuels, and materials (Ro, et al., Nature, 440: 940-943 (2006); Atsumi, et al., Nature 451, 86-89 (2008); Cane, et al., Science 282:63-68 (1998); and Weeks, et al., Biochemistry 50, 5404-5418 (2011)). However, the scope of innovation of living organisms is typically limited to functions that confer a direct advantage for cell growth, thereby maximizing biomass as the end product rather than a distinct molecule or reaction of interest. In contrast, synthetic biology approaches allow us to disconnect some of these remarkable biochemical transformations from cell survival and reconnect them differently for the targeted synthesis of alternative classes of compounds. One particularly interesting area of opportunity is the development of methods to introduce halides into complex small molecule scaffolds, which has become a powerful strategy for the design of synthetic pharmaceuticals. Indeed, it is estimated that 20-30% of drugs, including many of the top sellers, contain at least one fluorine atom (Müller, et al., Science, 317:1881-1886 (2007); D. O'Hagan, Chem. Soc. Rev. 37:308-319 (2008); and Furuya, et al., Nature, 473:470-477 (2011)). For example, tecent innovations have expanded the scope of synthetic CF bond forming methodologies, but the unusual elemental properties of fluorine that serve as the basis for its success also continue to restrict the range of molecular structures that can be accessed (Ball, et al., J. Am. Chem. Soc., 131:3796-3797 (2009); Watson et al., Science, 325:1661-1664 (2009); Rauniyar, et al., Science, 334:1681-1684 (2011); and Lee, et al., Science, 334:639-642 (2011)). As such, the invention of alternative routes for the site-selective introduction of halogens into structurally diverse molecules, particularly under mild conditions, remains an outstanding challenge.
In comparison to synthetic small molecules, halogens, e.g., fluorine, have limited distribution in naturally occurring organic compounds. For example, the only organofluorine natural products characterized to date consist of a small set of simple molecules associated with the fluoroacetate pathway of Streptomyces cattleya, a soil bacterium that houses the remarkable ability to catalyze the formation of CF bonds from aqueous fluoride (FIG. 1A) (Dong, et al., Nature, 427:561-565 (2004); and D. O'Hagan, J. Fluorine Chem., 127:1479-1483 (2006)).
The backbones of several large classes of medicinally-relevant natural products including polyketides, isoprenoids, steroids, alkaloids, eicosanoids, leukotrienes, and others are biosynthesized directly from the assembly and tailoring of simple acetate units (FIG. 1A). Introduction of the haloacetate monomer in place of acetate would allow incorporation of fluorine into the backbone of these targets and create new molecular function by combining the medicinal chemistry advantages of fluorine with the structural complexity and bioactivity of natural products. The present invention provides a method for accomplishing this goal.